TheN-Acyloxyiminium Ion Aza-Prins Route to Octahydroindoles:  Total Synthesis and Structural Confirmation of the Antithrombotic Marine Natural Product Oscillarin

Abstract

The first enantiocontrolled total synthesis of the marine natural product oscillarin is described. The proposed structure and absolute configuration of oscillarin is thus confirmed, and a previously assigned structure of a subunit was shown to be incorrect. The X-ray structure of an oscillarin-thrombin complex was resolved at 2.0 A resolution, which validated its potent inhibitory activity against the enzyme with an IC(50) = 28 nM. Methodology was developed for the synthesis of enantiopure octahydroindole-2-carboxylic acids with usable functionality at C-6. The method consists of the halocarbocyclization of N-acyloxyiminium ions containing an olefinic tether in the presence of tin tetrachloride or tin tetrabromide. This N-acyloxyiminium ion aza-Prins carbocyclization proved to be general for the construction of octahydroindole and perhydroquinoline 2-carboxylic acids. Mechanistic rationales are based on an antiperiplanar attack of the terminal alkene on the iminium ion, leading to an incipient secondary carbocation which is trapped by halide via an equatorial attack. X-ray crystal structures of products corroborate the expected stereochemistry.

Structure‐Based Organic Synthesis of Drug Prototypes: A Personal Odyssey

“…Our total synthesis of "the real" oscillarin (93) confirmed its structure and configurational identity. [170] Also rewarding was the inhibitory activity of our synthetic oscillarin against thrombin (IC 50 = 28 nm), which was the highest recorded among the known aeruginosins. A co-crystal structure with thrombin revealed the characteristic l-shaped architecture of oscillarin in the active site with the expected P 1 , P 2 , and P 3 site interactions.…”

“…The total synthesis [170] of this presumed structure was met with utter disappointment when testing revealed the lack of any inhibition of thrombin. In the interim, a second patent appeared [169b] in which the exact same structure was proposed with the 1-amidino-D-3,4-pyrroline as the end group (rather than the incorrect isomeric cyclic guanidine).…”

Natural Products Containing Medium‐Sized Nitrogen Heterocycles Synthesized by Ring‐Closing Alkene Metathesis

“…Hanessian et al recently described the total syntheses of dysinosin A (1) [15] that was isolated from a new genus of sponge of the family Dysideidae and oscillarin (2) [16] that was found in the algal cultures of Oscillatoria agardhii. Both alkaloids were constructed via two peptide couplings between three common subunits: an indolizidine carboxylic acid (4 or 6) derived from l-glutamic acid, an acyclic peptide chain (5 or 7) and pyrrolino-ethylamine 3 (Scheme 2.2).…”

Methods for the Chemical Synthesis of Noncoded α‐Amino Acids found in Natural Product Peptides

“…Since then many different aeruginosins have been discovered and isolated from natural sources [91]. Aeruginosins have grasped immediate attention in the scientific community due to possible uses as anticoagulants and anticancer agents [90,[92][93][94][95][96][97][98][99][100][101][102]. Aeruginosins are linear peptides containing a novel octahydroindole core, L-2-carboxy-6-hydroxyoctahydroindole (L-Choi), which is a noncoded CAA.…”